A novel homozygous variant in TRAPPC2L results in a neurodevelopmental disorder and disrupts TRAPP complex function.

Published on Sep 1, 2021in Journal of Medical Genetics4.943
· DOI :10.1136/JMEDGENET-2020-107016
Priyanka Ahimaz2
Estimated H-index: 2
(CUMC: Columbia University Medical Center),
Jacob J. Hagen3
Estimated H-index: 3
(CUMC: Columbia University Medical Center),
Wendy K. Chung39
Estimated H-index: 39
(CUMC: Columbia University Medical Center)
Background Next-generation sequencing has facilitated the diagnosis of neurodevelopmental disorders with variable and non-specific clinical findings. Recently, a homozygous missense p.(Asp37Tyr) variant in TRAPPC2L, a core subunit of TRAPP complexes which function as tethering factors during membrane trafficking, was reported in two unrelated individuals with neurodevelopmental delay, post-infectious encephalopathy-associated developmental arrest, tetraplegia and accompanying rhabdomyolysis. Methods We performed whole genome sequencing on members of an Ashkenazi Jewish pedigree to identify the underlying genetic aetiology of global developmental delay/intellectual disability in three affected siblings. To assess the effect of the identified TRAPPC2L variant, we performed biochemical and cell biological functional studies on the TRAPPC2L protein. Results A rare homozygous predicted deleterious missense variant, p.(Ala2Gly), in TRAPPC2L was identified in the affected siblings and it segregated with the neurodevelopmental phenotype within the family. Using a yeast two-hybrid assay and in vitro binding, we demonstrate that the p.(Ala2Gly) variant, but not the p.(Asp37Tyr) variant, disrupted the interaction between TRAPPC2L and another core TRAPP protein, TRAPPC6a. Size exclusion chromatography suggested that this variant affects the assembly of TRAPP complexes. Employing two different membrane trafficking assays using fibroblasts from one of the affected siblings, we found a delay in traffic into and out of the Golgi. Similar to the p.(Asp37Tyr) variant, the p.(Ala2Gly) variant resulted in an increase in the levels of active RAB11. Conclusion Our data fill in a gap in the knowledge of TRAPP architecture with TRAPPC2L interacting with TRAPPC6a, positioning it as a putative adaptor for other TRAPP subunits. Collectively, our findings support the pathogenicity of the TRAPPC2L p.(Ala2Gly) variant.
#9Andrea Ganna (Broad Institute)H-Index: 36
#10Daniel P. Birnbaum (Broad Institute)H-Index: 9
Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annot...
1,829 CitationsSource
#6Wendy K. Chung (Columbia University)H-Index: 8
Two siblings, one male and one female, ages 6 and 13 yr old, have similar clinical features of global developmental delay, multiple congenital anomalies affecting the cardiac, genitourinary, and skeletal systems, and abnormal eye movements. Whole-genome sequencing revealed a homozygous splice variant ({"type":"entrez-nucleotide","attrs":{"text":"NM_014462.3","term_id":"1519245917","term_text":"NM_014462.3"}}NM_014462.3:c.231+4A>C) in LSM1 that segregated with the phenotype in the family. LSM1 ha...
3 CitationsSource
#1Daniela Stanga (Concordia University)H-Index: 5
#2Qingchuan Zhao (UdeM: Université de Montréal)H-Index: 1
Last. Michael Sacher (McGill University)H-Index: 29
view all 6 authors...
: TRAPPC11 has been implicated in membrane traffic and lipid-linked oligosaccharide synthesis, and mutations in TRAPPC11 result in neuromuscular and developmental phenotypes. Here, we show that TRAPPC11 has a role upstream of autophagosome formation during macroautophagy. Upon TRAPPC11 depletion, LC3-positive membranes accumulate prior to, and fail to be cleared during, starvation. A proximity biotinylation assay identified ATG2B and its binding partner WIPI4/WDR45 as TRAPPC11 interactors. TRAPP...
28 CitationsSource
#1Michael Sacher (McGill University)H-Index: 29
#2Nassim Shahrzad (UCSF: University of California, San Francisco)H-Index: 6
Last. Miroslav P. Milev (Concordia University)H-Index: 9
view all 4 authors...
: The movement of proteins between cellular compartments requires the orchestrated actions of many factors including Rab family GTPases, Soluble NSF Attachment protein REceptors (SNAREs) and so-called tethering factors. One such tethering factor is called TRAnsport Protein Particle (TRAPP), and in humans, TRAPP proteins are distributed into two related complexes called TRAPP II and III. Although thought to act as a single unit within the complex, in the past few years it has become evident that ...
42 CitationsSource
#1Miroslav P. Milev (Concordia University)H-Index: 9
#2Claudio Graziano (UNIBO: University of Bologna)H-Index: 20
Last. Peter M. van Hasselt (UU: Utrecht University)H-Index: 26
view all 22 authors...
Background The combination of febrile illness-induced encephalopathy and rhabdomyolysis has thus far only been described in disorders that affect cellular energy status. In the absence of specific metabolic abnormalities, diagnosis can be challenging. Objective The objective of this study was to identify and characterise pathogenic variants in two individuals from unrelated families, both of whom presented clinically with a similar phenotype that included neurodevelopmental delay, febrile illnes...
26 CitationsSource
#1Ryan Poplin (Google)H-Index: 23
#2Pi-Chuan Chang (Google)H-Index: 12
Last. Mark A. DePristoH-Index: 48
view all 14 authors...
DeepVariant uses convolutional neural networks to improve the accuracy of variant calling. Despite rapid advances in sequencing technologies, accurately calling genetic variants present in an individual genome from billions of short, errorful sequence reads remains challenging. Here we show that a deep convolutional neural network can call genetic variation in aligned next-generation sequencing read data by learning statistical relationships between images of read pileups around putative variant...
340 CitationsSource
#1Falko Riedel (LMB: Laboratory of Molecular Biology)H-Index: 2
#2Antonio Galindo (LMB: Laboratory of Molecular Biology)H-Index: 13
Last. Sean Munro (LMB: Laboratory of Molecular Biology)H-Index: 67
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Originally identified in yeast, transport protein particle (TRAPP) complexes are Rab GTPase exchange factors that share a core set of subunits. TRAPPs were initially found to act on Ypt1, the yeast orthologue of Rab1, but recent studies have found that yeast TRAPPII can also activate the Rab11 orthologues Ypt31/32. Mammals have two TRAPP complexes, but their role is less clear, and they contain subunits that are not found in the yeast complexes but are essential for cell growth. To investigate T...
39 CitationsSource
#1Hussein Sheikh Ali Mohamoud (St. George's University)H-Index: 9
#2Saleem Ahmed (KAU: King Abdulaziz University)H-Index: 5
Last. Jamal Nasir (St George's, University of London)H-Index: 27
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Childhood onset clinical syndromes involving intellectual disability and dysmorphic features, such as polydactyly, suggest common developmental pathways link seemingly unrelated phenotypes. We identified a consanguineous family of Saudi origin with varying complex features including intellectual disability, speech delay, facial dysmorphism and polydactyly. Combining, microarray based comparative genomic hybridisation (CGH) to identify regions of homozygosity, with exome sequencing, led to the id...
20 CitationsSource
#1Isaac Marin-Valencia (HHMI: Howard Hughes Medical Institute)H-Index: 16
#2Gaia Novarino (Institute of Science and Technology Austria)H-Index: 16
Last. Joseph G. Gleeson (Boston Children's Hospital)H-Index: 91
view all 15 authors...
Background Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain. Objective We aimed to expand the range of neurodevelopmental disorders associated with mutations in T...
24 CitationsSource
#1Laura L. Thomas (Cornell University)H-Index: 4
#2J. Christopher Fromme (Cornell University)H-Index: 21
Rab guanosine triphosphatases (GTPases) control cellular trafficking pathways by regulating vesicle formation, transport, and tethering. Rab11 and its paralogs regulate multiple secretory and endocytic recycling pathways, yet the guanine nucleotide exchange factor (GEF) that activates Rab11 in most eukaryotic cells is unresolved. The large multisubunit transport protein particle (TRAPP) II complex has been proposed to act as a GEF for Rab11 based on genetic evidence, but conflicting biochemical ...
51 CitationsSource
Cited By2
#1Yu-Xiong Guo (Southern Medical University)H-Index: 1
#2Hong-Xia Ma (Southern Medical University)
Last. Qiong-Xiang Zhai (Southern Medical University)
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Background Intellectual developmental disorders (IDD) generally refers to the persistent impairment of cognitive activities and mental retardation caused by physical damage to the brain or incomplete brain development. We aimed to explore its genetic causes. Methods In this study, 21 IDD patients were recruited. The Gesell developmental scales (GDS) and Wechsler intelligence scale for children (WISC) were used to assess the impaired level of intellectual development for all probands. A supercond...
#1Bor Luen Tang (NUS: National University of Singapore)H-Index: 21
The early secretory pathway, provisionally comprising of vesicular traffic between the endoplasmic reticulum (ER) and the Golgi apparatus, occurs constitutively in mammalian cells. Critical for a constant supply of secretory and plasma membrane (PM) materials, the pathway is presumably essential for general cellular function and survival. Neurons exhibit a high intensity in membrane dynamics and protein/lipid trafficking, with differential and polarized trafficking towards the somatodendritic an...